The major histocompatibility complex (MHC) plays an essential role in the vertebrate immune system. MHC molecules bind foreign peptides and present them to T cells, thereby triggering an appropriate immune response. The MHC is a multi-gene family which includes a large number of loci. Some of these loci are among the most polymorphic loci known, while others are virtually monomorphic; and different MHC loci differ widely in their degree of expression. The evolutionary relationships among these loci are not well known, and MHC loci in different orders of mammals are not necessarily orthologous. The purpose of this proposed research is to understand the evolutionary mechanism responsible for maintaining the high polymorphism of certain MHC loci and to determine the evolutionary relationships among the major groups of MHC loci. The methods will involve statistical analysis of published DNA sequence data, of which there is now a substantial amount for the MHC of human, mouse, several other mammalian species, and the chicken. The following specific analyses are planned: 1) To test the hypothesis that MHC polymorphism is caused by overdominant selection relating to disease resistance. This will involve comparing the rates of synonymous and nonsynonymous nucleotide substitution in different regions of MHC genes. It is predicted that natural selection will enhance the rate of nucleotide substitution in codons encoding amino acid residues important for foreign antigen binding and recognition, and preliminary data support this prediction. 2) To study the evolution of poorly expressed MHC genes ( such as class I nonclassical genes) by determining rates of nucleotide substitution in regulatory sequences and in other functionally important region of such genes. 3) To make phylogenetic trees by an objective tree-making method in order to reconstruct the evolutionary history of the MHC and related genes.